Flexible and bioresorbable neural interfaces: self-powered biodegradable technologies for neuromonitoring and modulation

1 Introduction

Implantable medical devices have experienced a resurgence in the last couple of decades, both in terms of research and commercial use. Ever since the introduction of the cardiac pacemaker in the 1950s, surgeons and patients alike have become more inclined towards using implantable devices to treat physiological conditions (Fiandra, 1988). This is not an exception for the field of neurology and neurosurgery, where nowadays we can see Deep Brain Stimulation (DBS) and Vagal Nerve Stimulation (VNS) devices being commonly used for treatment of neurological conditions ranging from Parkinson’s Disease to epilepsy (Schachter and Saper, 1998; Frizon et al., 2018).

With regards to brain activity stimulation and recording, both for cortical and deep brain regions, perhaps one of the key advances was made by Wise et al. in the 70s when they introduced the Michigan neural probe, consisting of an array of microelectrodes in a Silicon shaft (Wise et al., 1970). This could also be said of the Utah array which uses a glass-silicon composite, similar to that of the Michigan probe in terms of stiffness and was presented in the 90s (Jones et al., 1992). Both of these devices represent a tipping point in the area of neural probe microfabrication and have become the gold standard for research in the field over the years. It can easily be said that they are the most well-known and used for pre-clinical and clinical tests, with both being used commercially in applications ranging from neuroprosthetics to spinal cord stimulation, which is of great importance in rehabilitation engineering (McGlynn et al., 2021; Wang T. et al., 2025).

Despite their efficacy and well-researched characteristics and applications, it should be noted that one of the main drawbacks of this technology is the fact that the probes are composed mainly of Silicon and/or Silicon composite materials. With Silicon having a Young’s Modulus of approximately 179 GPa, whilst brain tissue has one of 2 kPa, one can note that this mechanical characteristic mismatch could lead to issues in terms of the biointegration of the probe with the surrounding neural tissue, in particular in terms of causing excessive glial scarring (Polikov et al., 2005; Gulino et al., 2019). Such scarring could affect the performance of the microelectrodes, both recording and stimulating, since scar tissue possesses a different composition of cells and electrolytes, hindering the stimulation and recording of the surrounding neurons. Furthermore, the non-adaptive nature of these Silicon implants could lead to micromotions in the brain, which could in turn mean clinical complications leading to additional surgery.

It is because of the aforementioned facts that researchers have been moving towards a new sub-field within neural probe microfabrication, and that is the use of flexible, biocompatible polymers, such as Parylene-C, Polyimide and polydimethylsiloxane (PDMS) (Weltman et al., 2016). These polymers have a much lower Young’s Modulus than Silicon (in the range of 2–3 GPa) and, hence, have great potential for reducing glial scarring after implantation in the brain. In addition, they present researchers with the advantage of higher flexibility during design and fabrication compared to Silicon probes (Seymour et al., 2017).

In recent years, it was shown that Parylene-C could be used as the substrate material for a high density recording neural probe, with features as small as 2 microns, which demonstrates the ability of microfabricating flexible neural probes (Scholten et al., 2020). Polyimide has also been used quite extensively in the literature since the early 2000s (Rousche et al., 2001), where it was introduced as a biocompatible, flexible and easy to microfabricate material for use in a multichannel neural interface, and although the levels of electrode density demonstrated by some research groups are quite high, given the micron-scale dealt with, the ones that have been achieved with Parylene-C have not been obtained as of yet.

Notwithstanding, one should emphasize that these materials, although they provide better biointegration with the surrounding neural tissue and a decrease in the glial scarring caused after implantation; are still permanent materials that will most likely need to be retrieved through surgery at some point, in particular if we are talking about temporary treatment and recording avenues. This additional surgery, in turn, means that patients will be subjected to additional risks associated with invasive neurosurgery. Hence, scientists have been introducing in very recent years the possibility of using biodegradable biomaterials to comprise the bulk of neural probes, creating a new sub-field termed Transient Neural Probes (TNPs) (Fanelli and Ghezzi, 2021). It should be noted however, that these bioresorbable materials and devices are not necessarily a universal replacement for permanent neural probes, especially in conditions where chronic implantation is not just desirable but necessary, such as chronic brain computer interfaces (BCI) or long-term periprosthetic control. Transient devices, however, could be a complementary technology of particular attractiveness for applications that require recording and/or stimulation over a clearly defined therapeutic or diagnostic window. They could also provide a first point of temporary mapping and localisation for subsequent optimal implantation of permanent electrodes (e.g., DBS). This review, therefore, aims to shed light on the emerging field of transient or biodegradable neural electronics, as illustrated in Figure 1, focusing on four key aspects: the so-called medical “green” materials (both passive and active); their applications in recording and stimulation of neural activity; the naissance of bioresorbable power supply strategies (namely, wireless power transfer and energy harvesting) and the evaluation of these transient devices from a biological and clinical perspective. In addition to this, advantages and challenges present in this research field are highlighted with recommendations and future directions outlined.

2 Flexible and transient biomaterials

Transient green electronics, where devices intentionally disappear after a programmed duration, aim to leave minimal and harmless traces in the environment (Xu J. et al., 2019; Jiang et al., 2021). This represents a shift from conventional devices by embracing a predefined lifespan, after which they either partially or fully disintegrate. Said unique characteristic opens avenues for addressing critical issues such as electronic waste, in a multitude of sectors including soft electronics, wearable sensors, environmental monitors, hardware security systems, and implantable biomedical devices (Min et al., 2023).

Material selection for transient medical devices demands special considerations compared to conventional permanent ones. Not only must they be fabricated from biocompatible, conformable materials, but they must also degrade safely in their environment, with byproducts that are non-toxic and easily excreted from the body without causing harm. Two distinct categories of materials are used in bioresorbable electronics: “carrier materials” and “active materials”. Carrier materials serve as insulation and encapsulation for the device, while active materials are utilized to fabricate functional components such as electrodes and connecting cables. All these parts can be fabricated from organic or inorganic materials, each possessing their properties and use cases; with initial efforts done by research groups focusing on reducing the use of toxic materials, such as Pb, Cd and Hg, in electronic devices (Suganuma, 2001; D’Mellow et al., 2007; Wäger et al., 2012).

In terms of active materials, these can be subdivided into conductors and semiconductors. Regarding conductors, metallic materials were initially explored for their excellent conductivity. While most metals offer advantageous properties for medical electronics (e.g., Au and Pt), their non-biodegradable nature poses a challenge for fully sustainable solutions. Alkaline-earth and transition metals such as Mg, Ca, Zn, Fe and Mo are widely used as conductors in transient implants. They exhibit high biocompatibility and are dissolved and reabsorbed easily into nearby tissue by hydrolysis (Cha et al., 2019). On the other hand, their fast solubility (especially in the case of alkaline metals) results in a rapid degradation rate and reduced lifespan of the device (Cha et al., 2019). Tungsten, with safe and non-toxic properties, attracts attention for biodegradable devices (Bevers et al., 2009). Hydrolysis transforms these metals into stable ions, initiating oxidation, crucial for Mg, Zn, and Fe (Ryu et al., 2021). The corrosion rate, a key factor in electronic applications, is studied by analyzing degradation characteristics, particularly in thin-film electrodes, where rapid metal oxide formation precedes environmental dissolution (Yin et al., 2014).

Magnesium and Zinc are, as priorly mentioned, bioresorbable metals, with Mg exhibiting a rapid degradation (≈70 nm h⁻¹) in deionized water and Zn having a faster corrosion rate (≈7 nm h⁻¹) than other biodegradable metals like Fe, Mo, and W (Yin et al., 2014; Dang et al., 2019; Ryu et al., 2021; Cao et al., 2022). These characteristics make Mg and Zn advantageous for safe electronic applications and bioimplantable electronics. In fact, a fully bioresorbable device, utilizing Mg as the electrodes, with Poly-L-Lactic Acid (PLLA) as the piezoelectric layer, and Polylactic Acid (PLA) as the encapsulant, demonstrated excellent biocompatibility in experiments (Curry et al., 2018). On the other hand, despite Fe’s high biocompatibility, its slow corrosion rate limits its utility in applications requiring predictable rates, prompting research into alloying strategies, such as adding Sr, or combining Fe with less noble elements like Mn (Schinhammer et al., 2010). In contrast, Mo and W, with inherently slow corrosion rates, are suitable for fully bioresorbable electronics requiring predictable degradation rates and direct communication with biological tissues (Singh et al., 2020). This has been demonstrated by studies such as the one done by Fernandes et al., whereby they fabricated a bioresorbable electrochemical sensor with a bilayer of Mo and MoO_x as the electrodes, with post-deposition annealing, and were able to demonstrate improved stability of over 24 h (Fernandes et al., 2024).

A sub-category within conductors consists of conductive polymers (CPs), synthesized chemically and known for their eco-friendly characteristics, have gained attention for future green electronics. Additionally, C-framed conductive materials, characterized by their abundance, low cost, biocompatibility, and biodegradability, are ideal for fully transient medical electronics. CPs are categorized into intrinsic (ICPs) and composite (CCPs). Notable 1CPs, including polyaniline (PANI) and poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate) (PEDOT:PSS), which demonstrate good electrical conductivity and biocompatibility. However, the challenge lies in the biodegradability of ICPs due to the resistance of their long C and H bonding chains, prompting extensive research into methods for developing biodegradable ICPs (Akamatu et al., 1954; Bolto et al., 1963; De Surville et al., 1968; Shirakawa et al., 1977). CPs, specifically PEDOT:PSS, has been shown to be a promising alternative to metal conductors for developing biocompatible interfaces, particularly in neuronal interfaces (Yuk et al., 2020; Liang et al., 2021; Han et al., 2022). They demonstrate great flexibility, conductivity, biocompatibility, and most importantly commercial availability due to their low cost and uncomplicated fabrication process for large-scale production (Donahue et al., 2020). Moreover, PANI has similar merits to PEDOT:PSS in terms of ease of fabrication and electrical conductivity and can be used as an active material for electrical stimulation (ES) (Arteshi et al., 2018; Jadoun et al., 2021). In addition to this, zwitterionic CPs, which are based on a zwitterion, i.e., inner salt or dipolar ion, are also an attractive avenue for transient devices. These types of CPs present excellent conductivity, high biocompatibility and remarkable tunability through molecular design and surface modification techniques (Lin and Luo, 2022). They have been used as substitutes of polyethylene glycol (PEG) based drug delivery and pegylated therapeutics (Zhang et al., 2024). Key bioresorbable conductors and their properties are summarized in Table 1.

TABLE 1. Bioresorbable conductors, properties and applications.

With regards to semiconductors, Silicon (Si) has been the primary material of choice in the fabrication of semi-conductors, and although in bulk sizes Si does not dissolve quick enough to be deemed as bioresorbable material, in nanoscale Si has been shown to possess acceptable dissolution rates for use in transient implants (Hwang et al., 2012; Kang et al., 2016; Yu et al., 2016; Lee et al., 2017). Metal oxides such as ZnO and MgO have also been used as bioresorbable semi-conductors in transient implants (Dagdeviren et al., 2013). Furthermore, in terms of organic materials, natural and artificial organic biodegradable semi-conductors have been assessed. These organic semi-conductors exhibit an improved mechanical compatibility with their surrounding tissue due to their flexibility. Indigo (Irimia-Vladu et al., 2012) and melanin (Kim et al., 2013) have been used as natural semi-conductors in transistors and batteries while polypyrrole-based polymers, as artificial synthetic alternatives, have shown great promise due to their high biodegradability, versatility and thermal stability (Lei et al., 2017).

Moving on to the carrier materials, these provide a platform for the various components of the device as well as the encapsulation that shields sensitive materials from their environment, prolonging their lifespan, meaning that carrier materials play a crucial role in the development of transient devices. These materials hence serve as the foundation and protection for the device’s components, ensuring their proper functioning and longevity. Natural polymers including polysaccharides and polypeptides have been widely used in medical field for resorbable sutures for a long time and they have been proposed as insulation materials for transient electronics due to their well-established biocompatibility and safety (Ko et al., 2017; Kwon et al., 2018). Namely, Alginate is a gelatin heteropolysaccharide naturally found in brown seaweeds. Its gelatin-like texture has a viscosity similar to the extracellular matrix (ECM) and confers great integrability with host tissues. Alginate hydrogels and composites have been studied as biomaterials for tissue engineering and drug delivery systems that promote wound healing, as they can be incorporated with living cells and other ECM constituents (Ahmad Raus et al., 2021). Other green polymers such as silk (Hwang et al., 2012), cellulose (Jung et al., 2015) and chitosan (Hosseini and Lee, 2015) are natural and renewable materials that also fall into this category and offer high biocompatibility, softness and flexibility. In particular, silk has been a focus of research for the last 2 decades, owing to its exceptional biocompatibility, mechanical flexibility, high dielectricity, and ease of solution processing (Min et al., 2023). Silk can be used as a biomaterial in various ways in a device, serving as either the substrate or an active component. Impressively, silk can be processed into different morphologies and its degradation rate can be adjusted as well, making it an interesting material to explore for technological applications (Tao et al., 2012; Cerezo-Sanchez et al., 2023). Wang et al. reviewed silk-based materials for fabrication of soft bioelectronics. Due to its improved biocompatibility, robustness and large-scale sustainable production compared to specific synthetic polymers, silk has been demonstrated as a promising green alternative to those polymers to develop implantable electronics (Wang C. et al., 2019).

However, synthetic polymers are usually preferred over natural ones because of their reproducibility, customizability, and minimal cytotoxicity (Tanaka et al., 2014; Suhag et al., 2024). A great example of a transient synthetic polymer is poly(lactic-glycolic acid) (PLGA). PLGA is a copolymer of PLA and polyglycolic acid (PGA), demonstrating different dissolution rates based on the PLA-PGA ratio in its composition. This allows for precise control over the device’s lifespan which is imperative to the design of transient electronics (Hwang et al., 2014). Due to their eco-friendly synthesis and harmlessness, PLA, PLGA, and Polybutylene adipate terephthalate (PBAT) are promising for biodegradable electronics. PLA, derived from renewable resources, and PLGA, decomposing into metabolic byproducts, offer advantages for implantable devices (Hwang et al., 2014). PBAT, known as Ecoflex®, is a highly biodegradable synthetic polyester with good flexibility and biocompatibility (Witt et al., 2001). Asghari Niari et al. fabricated nanofibers using PLGA and PLGA-Polyethylene Glycol (PEG) and cultured them in human neuroblastoma cells (SH-SY5Y) (Asghari Niari et al., 2022). Their results demonstrated that both scaffolds increased cell viability, adhesion, and proliferation, with PLGA-PEG nanofibers showing improved results compared to PLGA-only fibers. The PLGA-PEG composite also increased the differentiation of SH-SY5Y cells to mature neurons, suggesting its suitability for neuronal regeneration. Another example of bioresorbable carriers or encapsulants are polyanhydrides such as poly(1,3-bis-(p-carboxyphenoxy, propane)), used in drug delivery systems. Due to their slow dissolution and erosion rates, they can prevent the rapid degradation of the device caused by biofluids, which is an advantage for devices intended for longer-term applications (Choi Y. S. et al., 2020).

A summary of the most commonly used semiconductors and carrier materials, their properties and applications can be found on Table 2.

TABLE 2. Bioresorbable semiconductors and carrier materials, their properties and applications.

3 Transient technologies for medical applications

Resorbable suture threads were one of the earliest implementations of transient materials in medical applications. These threads, usually made from animal or plant-based polymers, eliminate the need for suture removal by safely dissolving in the tissue within 6 months (Figure 2A) (Kang et al., 2016). A similar application can also be seen in resorbable surgical meshes, which offer support for tissues that are weakened or damaged during surgical procedures (Figure 2B) (Hjort et al., 2012).

Biodegradable stents have also been developed as an alternative to permanent metallic stents (Campos et al., 2013). Since they are designed to dissolve in tissue after a defined period, they can reduce long-term complications associated with conventional stents, such as thrombus formation and restenosis (Figure 2C) (Serruys et al., 2009).

Bioresorbable devices have also been explored for localized drug delivery (Kaveti et al., 2024). Compared to conventional systemic administration, they offer several advantages, including sustained and targeted release of therapeutic agents as the material degrades within the tissue. This approach can enhance therapeutic efficacy through local delivery while reducing systemic exposure, thereby lowering the risk of toxicity and off-target effects (Benhabbour et al., 2019).

A clinically established example is the use of implantable wafers composed of biodegradable polymers for the treatment of brain tumours. These devices are placed within the tumour resection cavity following surgical removal and release chemotherapeutic agents directly into the surrounding tissue as they degrade. This strategy bypasses the need for drugs to cross the BBB and avoids the limitations associated with systemic chemotherapy, which is often poorly tolerated by patients. Clinical trials have demonstrated the efficacy of this therapy, and it has received approval from the United States Food and Drug Administration (FDA) (Kleinberg, 2016).

To date, most clinical applications of biodegradable devices have focused on passive systems. However, the same transient design principle can be extended to active neurotechnologies, where biodegradable electronics may serve as temporary neural implants for monitoring or stimulation over defined therapeutic periods.

4 Transient neural probes for recording and stimulation

Despite significant advances in medical technology and research, many treatments for neurological disorders remain largely symptomatic, aiming to manage clinical manifestations and, in some cases, slow disease progression rather than achieve a definitive cure. The emergence of implantable neurotechnologies has expanded the therapeutic landscape, enabling direct interaction with neural circuits and offering new opportunities for both diagnosis and treatment of neurological and neuropsychiatric disorders (Sha and Du, 2024).

Neural interfaces have been widely employed in clinical settings for both diagnostic and therapeutic applications, with representative recording, stimulation, and bidirectional interfaces illustrated in Figure 3. They can incorporate a range of sensors to monitor physiological and biochemical parameters, including pressure (Kang et al., 2016), temperature (Salvatore et al., 2017), pH (Zhou et al., 2023), and electrical activity (Szostak et al., 2017). They can also be equipped with stimulatory components that deliver electrical signals to neurons, enabling modulation of neural activity within the implanted region (Koo et al., 2018).

Bioresorbable or biodegradable materials have also been explored in neural implant applications, particularly as temporary stiffening elements to aid the insertion of flexible, permanent neural probes. Within this context, several resorbable materials have been investigated, including silk fibroin, disaccharides, polyethylene glycol (PEG), and sodium alginate.

Among these, silk fibroin has been extensively studied due to its tunable dissolution kinetics, which can be adjusted from minutes to days depending on concentration and processing conditions. In addition, silk fibroin is readily sterilized and generates minimal antigenic byproducts upon degradation, making it a suitable candidate for transient stiffening applications (Kambe et al., 2020; Gunapu et al., 2021; Cointe et al., 2022). Disaccharides, such as maltose and sucrose, have been investigated as temporary stiffening materials for polyimide-based probes; however, they exhibit rapid dissolution kinetics, which may limit their applicability in certain contexts (Jeon et al., 2014; Xiang et al., 2014). Polyethylene glycol (PEG) is widely regarded as biocompatible and non-toxic, although concerns regarding its long-term stability and performance in vivo have been reported, highlighting the need for further investigation (Kozai et al., 2015). Similarly, sodium alginate offers favourable biocompatibility and mechanical properties comparable to brain tissue; however, its degradation behaviour and the effects of its byproducts in this application require further evaluation (Cerezo-Sanchez et al., 2023). Collectively, these observations suggest that materials currently employed as bioresorbable insertion aids may also hold potential as substrate materials for transient neural probes.

In line with this concept, Yu et al. developed a transient electrocorticography (ECoG) device capable of continuously monitoring cortical electrical activity for up to 30 days before undergoing resorption (Yu et al., 2016). The device successfully recorded interictal and seizure-like activity in murine models with performance comparable to conventional ECoG electrodes, while eliciting a reduced tissue response. Such systems hold promise for patients with refractory epilepsy, where temporary monitoring is required to guide surgical intervention (Engel et al., 2003).

In addition to neural recording systems, transient biomaterials have also been explored for post-surgical intracranial pressure (ICP) monitoring (Shin et al., 2018; Xu K. et al., 2019; Lu et al., 2020). This application is particularly important following brain tumour resection, where patients are at increased risk of elevated ICP (Kaal and Vecht, 2004; Rasmussen et al., 2004). Uncontrolled increases in ICP can lead to severe neurological damage and may be life-threatening if not promptly managed (Nakagawa and Smith, 2011). Kang et al. (2016), demonstrated a bioresorbable ICP sensor capable of continuous monitoring for up to 3 days, followed by gradual degradation over approximately 8 weeks in an animal model. The device utilized PLGA as the substrate, with silicon nanomembranes Si-NMs and (SiO₂) serving as the functional components. Using a similar platform architecture, the authors also developed temperature, pH, and motion sensors, highlighting the versatility of this approach for broader biomedical applications. Similarly, Shin et al. developed a bioresorbable optical sensing system that demonstrated in vitro biocompatibility and enabled in vivo measurement of intracranial temperature (ICT) and ICP in rodent models, with complete device resorption occurring within approximately 3 weeks (Shin et al., 2019).

In another study, Hwang et al. (2012), demonstrated a biodegradable implantable neural device, utilizing porous silicon and silk fibroin as the structural components, with magnesium (Mg) and magnesium oxide (MgO) serving as the conductive materials. The device exhibited rapid degradation, fully dissolving within approximately 10 min. In vivo implantation in the subdermal region of mice revealed no significant inflammatory response, highlighting its biocompatibility. In addition, Hosseini et al. demonstrated the potential of natural materials such as chitosan, derived from crustacean shells, to fabricate biocompatible resistive-switching memory devices, an important component for future implantable electronic systems (Hosseini and Lee, 2015).

Nonetheless, the field is not limited to naturally derived materials; synthetic biodegradable polymers, such as polycaprolactone (PCL) and poly(lactic-co-glycolic acid) (PLGA), have also been extensively investigated as substrate materials for transient neural probes and sensors. For example, Ferlauto et al. reported a neural probe based on a PCL substrate with microelectrodes composed of PEDOT:PSS doped with ethylene glycol (PEDOT:PSS:EG) (Ferlauto et al., 2021). In this study, the device enabled stable monitoring of neural activity in the mouse visual cortex over several months, significantly extending functional lifetime compared to devices based on naturally derived materials such as silk fibroin or chitosan, which typically operate on shorter timescales.

Thus far, the discussion has primarily focused on advances in neural recording technologies. However, neural stimulation has also demonstrated significant therapeutic potential in the treatment of neurological disorders. Deep brain stimulation (DBS) involves targeted electrical stimulation of specific brain regions and is used as an alternative therapy for patients who are refractory to pharmacological treatment. It has received approval from the United States Food and Drug Administration (FDA) for the treatment of conditions including essential tremor, epilepsy, Parkinson’s disease, dystonia, and obsessive-compulsive disorder (OCD) (Chen et al., 2013). Current DBS systems typically rely on permanently implanted electrodes that deliver electrical pulses to modulate neuronal circuits and restore functional activity within targeted regions (Gautam et al., 2018). Although effective, this approach is highly invasive and may require revision surgeries due to complications such as infection, lead displacement, or mechanical failure (Falowski and Bakay, 2016). In this context, flexible transient electrodes that can safely integrate with neural tissue and subsequently degrade may offer a promising alternative, with the potential to reduce long-term complications and eliminate the need for device removal.

Transient neural stimulation probes may initially appear limited in utility due to their biodegradable nature, particularly given that many neuromodulation applications target chronic conditions, such as Parkinson’s disease and epilepsy, that typically require permanent implants. Rather than serving as a direct replacement for permanent neural implants, bioresorbable stimulation probes are better understood as indication-specific devices whose degradation kinetics and electro-functional lifetime must be deliberately matched to the therapeutic window of the intended application. In this context, the days-to-weeks functional lifetime currently demonstrated by many transient devices may be insufficient for chronic neuromodulation but can be well suited to temporary clinical interventions. There is a growing body of evidence supporting the use of bioresorbable neuromodulation systems in clinical scenarios where only temporary intervention is required. Notable examples include post-stroke rehabilitation, traumatic brain injury, and peripheral nerve injury, where short-to medium-term stimulation (up to 3 months) can facilitate neuroplasticity and functional recovery (Li et al., 2010; Bao et al., 2020; Su and Xu, 2020; Harnisch et al., 2021; Baker et al., 2023). Supporting this concept, Fanelli et al. demonstrated the feasibility of transient neural probes for electrical stimulation. Longer-term stimulation protocols using a PCL-based probe with PEDOT:PSS:E.G.,:GOPS electrodes exhibited promising charge storage capacity (CSC) and charge injection capacity (CIC) in saline, key parameters governing the performance of neurostimulation electrodes (Boehler et al., 2020; Fanelli et al., 2022).

The application of neural implants extends beyond the central nervous system to the peripheral nervous system. Damage to peripheral nerves can result in long-lasting deficits that significantly impair patients’ quality of life. Peripheral nerve injury (PNI) most commonly arises from traumatic events or iatrogenic causes, such as surgical or medical interventions (Antoniadis et al., 2014; Alvites et al., 2018). PNI can lead to the loss of sensory, motor, or autonomic function in the affected nerve. Notably, in approximately one-third of cases, recovery is incomplete, resulting in persistent deficits such as muscle atrophy, weakness, and chronic pain; in more severe instances, this may progress to complete loss of function in the innervated tissue or organ (Wang M. L. et al., 2019).

The peripheral nervous system (PNS) exhibits a greater intrinsic regenerative capacity than the central nervous system (CNS) (BrosiusLutz and Barres, 2014). A wide range of biomaterials has been investigated to support and enhance neuronal regeneration in this context. Among these, nerve guidance conduits (NGCs) (Figure 4) are commercially available devices that have received approval from the FDA for the repair of short peripheral nerve defects (Kehoe et al., 2012). NGCs are tubular structures positioned between the proximal and distal stumps of a transected nerve, providing physical guidance and mechanical support for axonal regrowth across the injury gap (Vijayavenkataraman, 2020). These conduits are typically designed to support regeneration while minimising adverse tissue responses and degrading in situ following functional recovery (Fornasari et al., 2020). In addition, NGCs can be functionalised with growth factors, nutrients, cells, or neurotrophic agents, which have been shown to enhance axonal regeneration and improve overall repair outcomes (Jahromi et al., 2019).

The current gold standard treatment for PNI is autologous nerve grafting; however, this approach is associated with complications such as donor site morbidity, sensory deficits, scarring, and painful neuroma formation (Ijpma et al., 2006). Kornfeld et al. developed nerve guidance conduits fabricated from spider silk as a resorbable biomaterial, which degrade over approximately 3 months (Kornfeld et al., 2021). These conduits demonstrated comparable efficacy to autologous nerve grafts in supporting nerve regeneration, while avoiding the complications associated with autograft harvesting.

Neurostimulation represents an additional therapeutic approach for peripheral nerve injuries. Brief, low-frequency electrical stimulation has been shown to accelerate nerve regeneration and axonal growth in both animal and human studies (Gordon, 2016). This strategy is typically used as an adjunct to surgical repair and is most commonly applied intraoperatively for a short duration, often limited to approximately 1 hour following surgery (Ray et al., 2017). Implantable transient electrodes introduced during surgery offer the potential to extend electrical stimulation (ES) into the post-operative period, thereby enhancing axonal elongation and regeneration. In this context, Koo et al. reported a bioresorbable cuff electrodes designed for peripheral nerve applications, demonstrating functional nerve recovery with wireless control of stimulation parameters over a 6-day period (Koo et al., 2018). Beyond electrical approaches, peripheral nerve regeneration has also been achieved using optical stimulation. Sun et al. developed transient optoelectronic stimulators capable of activating the sciatic nerve in rodents and the facial nerve in rabbits (Sun et al., 2024). Their device, composed of a PLLA–poly (trimethylene carbonate) (PTMC) copolymer substrate with Mo electrodes and Si p–n junction diodes interfacing with the nerve, exhibited complete degradation after approximately 40 days in PBS. Collectively, these studies highlight the versatility of transient materials for neural modulation, demonstrating their applicability not only for electrical stimulation but also for alternative modalities such as optoelectronic activation.

Shifting focus to the spinal cord, injuries are commonly associated with long-term disabilities, including paralysis, loss of voluntary motor control, and chronic pain. These conditions are often irreversible and remain refractory to current therapeutic approaches, such as surgical intervention and long-term pharmacological management. Emerging therapeutic strategies for spinal cord injury (SCI) include the use of implantable devices capable of recording and stimulating spinal cord neural activity, thereby enabling modulation of neural circuits within the spinal cord.

Neuromodulation has been utilized to treat pain for decades and it has gained attraction for its safety and low side effects. Failed Back Surgery Syndrome (FBSS) is a term used to describe the persistent pain and discomfort that persists even after surgical procedures intended to alleviate these symptoms have been performed (Thomson, 2013). There has been significant evidence of spinal cord stimulation being effective for pain relief in patients with FBSS (Grider et al., 2016).

Just as the measurements of intracranial pressure in cases of traumatic brain injury are valuable, intraspinal pressure (ISP) could also serve as a useful indicator of patients’ condition in events of traumatic spinal cord injury (TSCI) (Phang and Papadopoulos, 2015). Werndle et al. demonstrated that subdural intraspinal pressure at the injury site can be measured safely using a pressure probe placed in subdural space. They found that the ISP at the injury site was higher than either the subdural pressure below the injury or the extradural pressure (Werndle et al., 2014). Measurements were started within the first 72 h following the onset of the injury and continued durations for up to a week. This presents another potential application for transient implants that could be engineered to continuously measure ISP for a determined amount of time and safely dissolve afterwards.

The challenge in designing probes for the spinal cord comes from its special viscoelastic properties. The spinal cord has a Young’s modulus of 0.25 MPa–0.3 MPa. It is flexible and it endures significant compression and deformation during natural body movements (Cheng et al., 2008). These mechanical properties present a challenge for engineering probes and devices. These devices must be flexible enough to integrate into the spinal cord, yet robust enough to withstand the strains caused by movements within the cord. For this reason, flexible and stretchable materials are of great interest for fabrication of medical implantable devices. Moreover, flexible neural probes elicit a reduced foreign body reaction compared to stiff probes and offer improved mechanical compatibility with the tissue (Canales et al., 2015; McGlynn et al., 2021). Lu et al. demonstrated successful recording and optical stimulation of the rat spinal cord using flexible and stretchable fibres. They recorded electrophysiological activity for up to 1 week in freely moving mice, while the fibres maintained their performance and structure under movements of the spinal cord (Lu et al., 2017). The translation of these into transient devices through the use of a transient substrate rather than PDMS, could potentially improve the clinical outcomes through the elimination of retrieval surgeries, providing a platform for temporary treatment of spinal cord injury.

As an overview, Figure 5 showcases an estimated timeline of the degradation of materials explored in Section 2, mapped out against different clinical indications for neural recording and stimulation, both in the CNS and PNS, as well as against the timeline for different key events in the foreign body response following device implantation.

However, one of the key disadvantages of these bioresorbable materials is the fact that because of their biodegradable nature, they pose a problem when trying to fabricate them through traditional microfabrication protocols, such as photolithography, which uses harsh chemicals, such as tetramethylammonium hydroxide (TMAH) or Cyclopentanone, to develop the desired microelectrode and/or probe patterns on the desired substrate material (McGlynn et al., 2022; Walton et al., 2022). It is perhaps because of this that most researchers in the field have stuck to alternative methods of microfabrication, such as soft lithography techniques, stencil lithography and 3D printing (Singh et al., 2020; Ferlauto et al., 2021; Fanelli et al., 2022; Fumeaux and Briand, 2024). Nevertheless, this distancing with traditional photolithography methods implies that the resolution that can be achieved is reduced significantly, in particular during the microelectrode fabrication process, hindering single-cell monitoring and treatment.

One recent study done by Bathaei et al. suggests that the use of a protective layer, in this case Dextran, on top of the bioresorbable polymer PLA, could perhaps allow for the use of photolithography techniques to fabricate biodegradable electronics (Bathaei et al., 2023). In this study the authors were able to showcase the successful microfabrication of commonly used electronic components, such as capacitors, resistors and inductors. It is even suggested that although the work focused solely on micron-scale features and devices, a similar protocol could be employed to fabricate transient electronic devices in the sub-micron scale, utilizing e-beam lithography techniques rather than photolithography. Such a study demonstrates the potential of the field of transient bioelectronics, simply by adapting current photolithography and e-beam lithography fabrication methods to protect the bioresorbable materials from the harsh chemicals used for development and patterning.

One other fabrication avenue that is being explored is the use of laser ablation and laser cutting equipment (Shim et al., 2019; Janićijević et al., 2024). The use of laser ablation presents the following unique advantages: it is much more cost-effective that other cleanroom equipment, for example, dry-etching machines which are labor intensive with multiple gas requirements to perform the etching, which in turn means that they are considerably slower than laser cutting equipment. Furthermore, because of the ease of use and fabrication of the latter, this means that the optimization of the etching parameters and process is faster and easier, allowing for a quicker turnaround rate. This is a key aspect to take into account when thinking of large-scale fabrication and future commercialization of the devices. On the other hand, there are definite downsides to using this technology compared to the more traditional methods of dry and wet etching. One of these would be the resolution of the equipment hindering the production of micron-scale devices. Current typical equipment, utilizing CO₂, is not capable of achieving anything less than 5–25 µm features (Kumar et al., 2023), depending on the wavelength employed, which can become an issue if one aims to fabricate neural probes to perform single-neuron recordings. The feature size obtainable is hence more suited towards the stimulation-side of devices as well as neural recordings that are performed over a larger brain region. Table 3 compares the principal candidate routes in terms of resolution, throughput, cost, reproducibility, material compatibility, and risk of processing-induced degradation.

TABLE 3. Overview of fabrication methods for biodegradable and bioresorbable materials used in medical devices and implants, including neurotechnology.

5 Transient power supply strategies

5.1 Transient energy harvesters (TENGs and PENGs)

One of the crucial challenges associated with these implantable neural devices, however, lies in the provision of a reliable and sustainable power source to ensure their long-term functionality. Some of the problems using traditional battery solutions present limitations in terms of lifespan, size, and the need for replacements over the time, leading to increased risks and inconvenience for patients/users. In response to these challenges, energy harvesting technologies have emerged as a transformative solution, promising to revolutionize the landscape of implantable medical devices.

Energy harvesters have recently emerged as a novel method to power implantable medical devices by harnessing energy from the surrounding environment or natural vibrations, as shown in Figure 5A. This energy might be from various forms, such as mechanical vibrations, changes in thermal gradients, or radiofrequency (RF) signals.

There are four types of energy harvesters: piezoelectric nanogenerators (PENG) (Wang and Song, 2006; Wang et al., 2018), triboelectric nanogenerators (TENG) (Zhu et al., 2012; Kim et al., 2020; Ning et al., 2022), thermoelectric nanogenerators (TEG) (Han et al., 2023), and Photovoltaic (PV) energy harvesters (Dagar et al., 2018), which can efficiently convert energy from one form to another with minimal losses as shown in Figure 5B. Recently, PENG and TENG devices have attained significant attention as energy harvesting devices to conform a self-powered power supply. PENG devices simply follow the sandwich structure with a piezoelectric layer embedded inside the two conducting metal layers with the main operating principle, namely, the piezoelectric effect (Gao et al., 2024). The piezoelectric effect is the phenomenon that occurs when pressure or mechanical force/stress is applied on a piezoelectric material causing the distribution of the electric charge within the material resulting in a change in potential. Similarly, TENG devices mainly work on the principle of the triboelectric effect, which mainly occurs due to the contact and separation of the materials (electropositive and electronegative) with different electronegativities (Zheng et al., 2016; Jiang et al., 2018). There are primarily four steps involved, namely, the contact electrification, separation, potential generation, and load connection. Initially, when an electropositive material comes into contact with the electronegative material, the atoms on the surface interact with each other and there will be a charge transfer occurring between them. Next, after the separation there will be positive and negative polarities formed on the surface of the materials owing to the difference in the electron affinities. This separation of the charges creates an electric potential between the materials, resulting in energy that can be outputted.

5.1.1 Flexible, biodegradable and stretchable materials for TENG and PENG

Numerous materials, both synthetic and natural, have been investigated for the development of Triboelectric and Piezoelectric Nanogenerator devices. Notably, biomaterials like chitosan, cellulose, and silk fibroin have emerged as highly effective active layers, serving as piezoelectric layers for PENG applications and electropositive layers for TENG devices (Jiang et al., 2018). These biomaterials exhibit exceptional qualities such as flexibility, biocompatibility, and biodegradability.

Recently, An et al. has demonstrated a flexible and implantable PENG device to harvest energy from the biomechanical movements of the living porcine heart which is shown in Figure 6 (An et al., 2024). The PENG device generates a maximum current of 20 µA from the contraction and relaxation of the heart and in the near future, this kind of self-powered in vivo electronic device could play a crucial role in eliminating the large bulky batteries and in reducing the extra costs related to the overall system. Even though the authors suggest the use in cardiac applications, it should be noted that such a system could be of great use in neural applications, in particular for spinal cord and peripheral nerves recording and stimulation scenarios. In addition, another study shows a PENG device the was crafted using one-dimensional Zinc Oxide (ZnO) nanowires grown on flexible and biodegradable cellulose paper, featuring a sandwich structure with Au/Cellulose serving as the top and bottom electrodes (Kim et al., 2011). This PENG device demonstrated an impressive and stable piezoelectric current density of approximately 2uAm⁻², showcasing enhanced mechanical flexibility and thermal stability due to the inherent mechanical properties of cellulose paper. This study unequivocally establishes cellulose as a promising substrate for future PENG-based energy harvesting applications, offering advantages such as cost-effectiveness, lightweight nature, flexibility, and thermal stability; as well as its established biocompatibility, making it a suitable candidate for energy harvesters in implantable medical and neural devices (Teng et al., 2023).

Another notable advancement involves the development of a transient TENG device utilizing bioresorbable silk fibroin for real-time, in vivo monitoring and therapeutic treatment of epileptic seizures (Zhang et al., 2018). Beyond energy harvesting, the programmable degradation rates of silk fibroin, influenced by factors like degumming times and post-treatment methods such as annealing, make it suitable for implantable neural applications.

Moreover, composite materials, including synthetic-natural polymer composites and hybrid organic-inorganic nanocomposites (e.g., silk fibroin-ZnO nanorods, chitosan-iron nanoparticles), have exhibited significantly enhanced piezoelectric properties. For instance, a study focused on combining silk fibroin with ZnO nanoparticles to explore a nanogenerator for energy harvesting applications (Sarkar et al., 2022). The device generated a maximum open circuit voltage of 25 V for a Silk: ZnO ratio of 9:1 and demonstrated a maximum output power density of 7 mWcm⁻² further demonstrating it is an excellent candidate for the next-generation biomaterial-based energy harvesters. Similarly, other biodegradable materials like chitosan and collagen have shown promise for PENG/TENG-based medical and implantable energy harvesting applications (Charoonsuk et al., 2021; Gao et al., 2023; Son and Park, 2024; Zhao et al., 2024).

The integration of degradable biomaterials in implantable energy harvesting applications presents promising opportunities, yet several challenges must be navigated for successful implementation. Biocompatibility and biodegradability are paramount considerations, demanding materials that not only harmonize with the physiological environment but also undergo controlled degradation over time. The mechanical strength and durability of biomaterials need enhancement to withstand the dynamic conditions within the human body. Moreover, overcoming the inherent poor electrical conductivity of many biomaterials without compromising biocompatibility is a critical challenge. Specialized fabrication techniques are required to shape biomaterials into functional devices, necessitating cost-effective and scalable methods. The integration of biomaterial-based energy harvesters with electronics presents challenges in compatibility, interface design, and reliability. In addition to this, regulatory approval and standardization pose hurdles, necessitating adherence to stringent safety and efficacy standards for clinical translation.

5.1.2 Strategies for performance enhancement in TENG/PENG devices

Hybrid Materials and Structures for Improved Performance:

The selection of appropriate materials and their combination into composites allows for the tailoring of properties crucial for energy harvesting applications. Various elastomeric materials like PDMS, Ecoflex®, thermoplastic, etc., combined with the 1D nanowires, nanotubes, nanofibers, etc., such as the metallic nanowires like silver nanowires, copper nanowires, gold nanowires, etc., have proved as excellent materials for stretchable and flexible electrode materials. Notwithstanding, these materials do not fall in the biodegradable, transient category, therefore, researchers have been evaluating degradable composites for their use in PENG/TENG devices. In a study performed by Baburaj. et al., they investigated the performance of a Zinc Oxide nanoparticles and hydroxypropyl methylcellulose (HPMC) composite, obtaining a maximum output voltage of 39.8 V and 4.30 µA current, with a power density of 0.23Wm^−2, for the 1% HPMC:ZnO composite (Baburaj et al., 2024). This device fully degraded after 36 h and the authors have pointed out the potential of HPMC as not just a biodegradable component in energy harvesting devices, but also as a biocompatible material due to its low in vivo rejection reported (Shetty et al., 2015).

5.1.2.1 Post-treatment approaches and surface modifications

Post-treatment methods like thermal, plasma, optical, acid treatments, etc., also play a crucial role in enhancing the output performance of energy harvesting devices. Recent studies have demonstrated that doping and thermal treatment of calcium bismuth niobate has shown excellent improvement in terms of the d₃₃ coefficient owing to the reduction in grain size and domain wall density (Luo et al., 2023). Additionally, Ico et al. have prepared poly(vinylidene fluoride trifluoroethylene) (P(VDF-TrFE)) based 1D nanofibers using electrospinning, towards energy harvesting applications, generating a peak-to-peak voltage of 39V and output power of 75 mW. The post thermal treatment of the nanofibers at 90 °C for 24 h demonstrated excellent improvement in the d₃₃ values as compared to pristine nanofibers (Ico et al., 2018). The significant improvement in d₃₃ might be due to the dimensional reduction of the nanofibers and dipole alignment inside the PVDF-TrFE. Another work on Barium Titanate has demonstrated enhanced piezoelectric as well as pyroelectric properties after thermal treatment (Elbasset and Sayouri, 2015). Results demonstrate that the d₃₃ coefficient linearly increased till 900 °C and was stable afterwards and that the pyroelectricity increases exponentially above 900 °C. However, due to these high temperatures, thermal treatment is perchance not the most adequate way of modification for transient and biodegradable TENG/PENG devices, since most biodegradable materials will not withstand these high temperatures. A low-temperature curing process over a longer period of time is therefore better suited for transient materials.

Furthermore, surface engineering such as surface pattering, surface treatments, surface functionalization or chemical treatments on the surface can enhance surface charge density by increasing the overall contact area of the energy harvester thereby resulting in an improved overall current or power density. As an example, Zhang et al. adopted the surface patterning, i.e., fabrication of high dense micro/nanostructures on the surface of a triboactive layer (PDMS), using a soft lithography technique (Zhang et al., 2013). The performance of the TENG, i.e., both the open circuit voltage and short circuit current, are greatly enhanced owing to the increase in the roughness of the friction surfaces. Another work showcased an enhanced TENG output voltage using a simple surface texturing technique, exploiting a sandpaper technique, based on the soft lithography approach (Vivekananthan et al., 2020). The device exhibited excellent electrical output voltage of 370 V and maximum current of 6 mA with the overall power density of 17 mWm⁻² at a load resistance of 1GΩ. These same techniques could be applied to transient materials, whereby, nanostructures and increased surface roughness in the biodegradable triboelectric layers could be obtained through soft lithography, O₂ plasma treatment or 3D printing.

5.1.2.2 Advances in fabrication techniques

Various novel fabrication techniques including additive manufacturing, advanced thin-film deposition, roll-to-roll processing, smart manufacturing, and bio-fabrication, signify a transformative era for TENG and PENG devices. Traditionally, techniques such as drop casting, spin coating, spray coating, electrospinning, electrochemical deposition, etc., have been utilized for the fabrication of TENG/PENG devices. More novel methods such as Chemical Vapor Deposition (CVD), Physical Vapor Deposition (PVD), and Atomic Layer Deposition (ALD) have become pivotal in coating and engineering thin films with tailored properties. These techniques are particularly advantageous for achieving precise thickness control and uniformity, essential for optimizing the performance of TENG/PENG devices. Moreover, advancements in microfabrication and nanofabrication processes have enabled the miniaturization of energy harvesting components, paving the way for the development of compact and portable devices with enhanced power generation capabilities. As an example, roll-to-roll processing stands out as another transformative fabrication approach for TENG/PENG applications. This continuous manufacturing technique allows for the cost-effective production of energy harvesting devices on flexible as well as bioresorbable substrates. Furthermore, the integration of smart manufacturing and Industry 4.0 principles continues to further the advancement of fabrication techniques, introducing real-time monitoring, control, and optimization of TENG/PENG device production processes.

5.1.2.3 Printing techniques

Printing techniques (Figure 7) prove invaluable for implantable and biodegradable energy harvesters, allowing for precise customization of device shapes and features to meet individual anatomical requirements. Additionally, printing techniques support rapid prototyping, enabling iterative design improvements, while the flexibility of materials accommodates the dynamic nature of biological tissues. The unique capabilities of printing techniques empower the creation of custom and intricate structures with complex geometries, a feat often unattainable through conventional manufacturing methods and this feature is particularly critical for optimizing the efficiency of TENG devices by tailoring their geometric features. The selection of materials and the ability to create composite structures through 3D printing offer a means to enhance the mechanical and electrical properties of TENG/PENG components.

Various 3D printing methods have been recently employed for the fabrication of TENG and PENG devices. These methods include fused deposition modelling (FDM), direct ink writing (DIW), stereolithography (SLA), and digital light processing (DLP). FDM, known for its simplicity and cost-effectiveness, involves heating a thermoplastic filament above its glass transition temperature at the nozzle. The molten material extrudes onto the substrate and solidifies as it cools. While FDM is advantageous for its ease of use, it has limitations in terms of material variety, mechanical properties, and functional capabilities. Direct ink writing (DIW) utilizes a syringe filled with liquid or paste, controlled by software to move in the x, y, and z directions. Simultaneously, curing methods like UV curing, thermal curing, or solvent evaporation take place in a closed chamber during the printing process. In the case of DLP-based printing, polymers containing photo-initiators serve as the printing ink. UV curing occurs in a closed UV chamber after each layer is printed either from the bottom or the top side of the chamber. For instance, a three dimensional (3D) ultra-flexible TENG device was fabricated using additive manufacturing technique, i.e., hybrid UV 3D printing which generated a maximum output power per unit volume of 11 Wm⁻³ (Chen et al., 2018). Furthermore, a self-powered wearable device application of LED glow, self-powered SOS flickering and buzzing distress signaling system was shown as a proof of concept (Chen et al., 2018). This shows the potential for transient TENGs, whereby the resin could be composed of a biodegradable and biocompatible material. Similarly, Li et al. proposed an all-printed energy harvester and a self-powered pressure sensor basing the TENG device on a rice paper substrate (Li et al., 2020). The active layer of the TENG device was fabricated using a direct laser writing technique and the electrodes were prepared using the inkjet printing. Utilizing cutting-edge printed technology in ongoing research creates opportunities for the development of innovative transient energy harvesting devices.

However, there are some of the challenges associated with printing technologies for energy harvesters: 1) Achieving consistent and reliable performance from printed energy harvesting devices presents a challenge. Factors such as layer adhesion, material degradation, and structural integrity need to be carefully addressed to ensure the durability and reliability of printed components, especially in dynamic or harsh environments. 2) The resolution and precision limitations of current printing technologies may hinder the fabrication of intricate structures necessary for optimizing energy harvesting efficiency. Overcoming these limitations requires advancements in printing technologies or the development of hybrid approaches. 3) Establishing standardized processes for printing in energy harvesting applications is essential for ensuring consistency, quality, and performance across different manufacturing setups. Implementing effective quality control measures to identify and rectify defects is a challenge in the complex, multi-material printing landscape. Addressing these challenges will contribute to the successful integration of printing technologies into energy harvesting applications, fostering advancements in sustainable and efficient energy solutions.

5.1.3 Recent advances in transient, biocompatible TENGs and PENGs

TENG/PENG devices stand as promising solutions for transient neural probe applications owing to their capacity to harness mechanical energy within the human body as well as other various applications (Figure 8). These devices offer a self-sustaining power source for neural probes, adept at capturing delicate neural signals without requiring bulky external power supplies. Their high sensitivity to minute mechanical stimuli ensures efficient conversion of bodily movements, like the heartbeat or muscle contractions, into stable electrical energy for neural probes. With the ability to be miniaturized and tailored for biocompatibility, TENG/PENG devices seamlessly integrate into neurotechnology, offering an autonomous and enduring power supply, reducing the need for frequent replacements or invasive procedures. This also enables continuous, precise, and uninterrupted data collection, vital for real-time monitoring and analysis of neural activities in healthcare and research. The self-powered, compact nature of these devices not only minimizes invasiveness but also enhances the portability and versatility of neural probes, widening their potential applications in various environments and settings.

Recently, Tian et al. demonstrated a Transient Supercapacitor (TSC) using a zinc-polypyrrole (Zn@PPy) composite that exhibited a maximum energy storage density of 0.394 mWhcm⁻² (Tian et al., 2021). Additionally, the TSC was found to be completely degraded in PBS solution within 30 days. In vivo degradation studies were conducted by implanting the TSCs into the subcutaneous regions of rats, and the devices disappeared completely after 30 days of implantation. Subsequent biocompatibility tests were performed on silk-encapsulated zinc (Zn), silk-encapsulated Zn@PPy, and pure silk fibroin, all of which demonstrated excellent biocompatibility for the prepared samples. The proposed innovative TSCs utilizing a zinc-polyproline composite presents a promising avenue for energy storage in implantable devices. However, the observed rapid degradation in physiological conditions and subsequent fast disappearance after in vivo implantation underscore the need for further research to enhance device stability, in particular for longer term applications. The demonstrated biocompatibility of encapsulated materials opens avenues for continued exploration, emphasizing the importance of refining transient energy storage systems for sustainable and reliable implantable applications. Similarly, another work on degradable and biocompatible SCs was prepared using a sericin-based hydrogel and demonstrated a very good energy density (volumetric) of 26 uWcm⁻² and high specific capacitance with good retention after long term charging and discharging (Lv et al., 2023). Further, both in vitro and in vivo studies were performed and demonstrated the lighting of an LED by connecting the SCs in tandem. Moreover, Sheng et al. have demonstrated a work on a high-performance implantable SC exhibiting tunable degradation, excellent biocompatibility and good mechanical flexibility (Sheng et al., 2021b). In addition, the SC uses a 2D and amorphous molybdenum oxide (MoO_x) as the electrode material grown on the Mo foil using a green electrochemistry technique. The SC exhibits high areal capacitance of 112.5 mFcm⁻² at 1mAcm⁻² and a good energy density of 15.64 uWhcm⁻². In another study conducted by Lee et al., a serpentine-shaped wire SC was devised using Mo for the wire and a biodegradable elastomer (poly(1,8-octanediol-co-citrate)/POC) as the substrate, with the wire being anodized, to improve the electrochemical capacitance, and coated with an electrolyte composed of NaCl/PVA (Lee et al., 2019). They were able to demonstrate a facile fabrication method for an SC, with an adequate stable performance under up to 50% strain. Moreover, the SC demonstrated an aerial capacitance of 4.15 mFcm⁻² at 0.05mAcm⁻², an energy density of 0.37uWhcm⁻² and a power density of 0.8mWcm⁻². Similarly, additional works on SC have reported excellent performance in terms of charge storage capacity, superior energy and power density, low equivalent series resistance (ESR) and excellent cyclic stability using a range of traditional cleanroom-based fabrication methodologies as well as in situ hydrolysis (Sheng et al., 2021a). Results for biodegradable Zn-ion hybrid supercapacitors that use molybdenum sulfide (MoS₂) nanosheets as a cathode, ion-crosslinked alginate gel as electrolyte, and zinc foil as anode, achieved high capacitance (93.5 mF cm⁻²) and an output voltage (1.3 V) (Sheng et al., 2023). Another study focused on MoO_x electrodes had results demonstrating an areal capacitance of 112.5 mF cm⁻² at 1 mA cm⁻² and an energy density (15.64 μWh cm⁻²) (Sheng et al., 2021b). All the aforementioned studies demonstrate the continuous improvements in the field, with more rapid and facile fabrication methods, as well as diverse energy and power outputs to accommodate for the various applications within the implantable medical devices and neurotechnology realm.

On another note, power management circuits (PMCs) are essential for TENGs and PENGs due to the variable and intermittent nature of the electrical outputs generated from mechanical energy sources. These devices, designed to convert mechanical vibrations or movements into electricity, often produce power with fluctuating voltage and current characteristics. To address this variability, PMCs play a crucial role in regulating and stabilizing the output, making it suitable for powering medical electronic devices or systems. Additionally, TENG and PENG devices benefit from PMCs for efficient energy harvesting, energy storage, and voltage regulation. These circuits help match the power characteristics of the energy harvesting source with the requirements of the connected load, ensuring optimal power transfer and utilization. Furthermore, s can incorporate components for energy storage, such as batteries or capacitors, as the ones previously mentioned, offering overcharging and overdischarging protection to enhance the overall reliability and longevity of the energy harvesting system. Recently, Song et al. showcased a wearable TENG device utilizing flexible printed circuit boards (Song et al., 2020). This device is freestanding and incorporates a PMC. The PMC system integrates the standalone TENG, a bridge rectifier to convert the TENG’s AC output into pulsating DC voltage, energy harvesting Integrated Circuits (ICs) to generate the desired output DC voltages and currents, a voltage regulator to ensure a constant and regulated DC output voltage, and Bluetooth connectivity linked with biosensors (sweat sensors) to facilitate wireless data transfer.

5.2 Transient wireless power transfer (WPT)

As priorly mentioned, a critical premise for the seamless operation of medical, and in particular neural implants, lies in ensuring a sufficient power supply to support their functionality.

As an alternative to energy harvesters, Wireless power transfer (WPT) offers a dependable and customizable power supply, enabling the continuous powering and recharging for implantable devices (Zhang et al., 2022a). A WPT system specifically designed for powering implantable devices typically consists of two subsystems: external transmitter and implantable receiver, as illustrated in Figure 9. The radio frequency (RF) power provided by a signal generator is transmitted via an external transmitter antenna, propagating through the air and tissue, and subsequently captured by the receiver implantable antenna, where it is stored in an energy storage module (Zhang et al., 2022b). However, the RF signal cannot directly support implant loads. Therefore, a rectifier circuit is indispensable to convert the RF signal to usable DC power (Zhang et al., 2023b). Specifically, to minimize the implantable volume, a single diode is typically adopted to rectify the RF power.

WPT technology includes near-field coupling, mid-field and far-field radiation transmit strategies, enabling the transmission of the energy in the form of electromagnetic (EM) waves through a medium. In general, the non-radiative or near-field WPT systems operate in the low frequency region (below MHz range) to minimize loss and localized overheating in the human body (Zhang et al., 2022a). However, the low frequency antennas exhibit a low gain value, relatively large size, and limited bandwidth (BW), hindering their application for wireless data communication with implantable devices. Particularly, near-field WPT offers relatively higher power transfer efficiency but greatly suffers from short transmission distances and lateral, and angular misalignment (Zhang et al., 2023a). In comparison, mid-field WPT and far-field WPT are less affected by the misalignments between the transmitter and receiver over a longer distance. However, they are constrained by low power transfer efficiency due to multipath losses.

Additionally, EM waves can serve as the signal carriers for data transmission in the radio and/or microwave region. This eliminates the need for transcutaneous leads to relay the data collected by the incorporated biosensors for accessing the neural activity, such as intracranial pressure sensors (Mitchell et al., 2020). However, permanent implantation of rigid electronics devices is susceptible to triggering the immunological side-effects, and the device must undergo retrieval through surgery once it fulfils its assigned tasks. Recent advances in flexible and transient electronics provide an innovative solution for brain implants with a predefined lifespan (Fanelli and Ghezzi, 2021; Cerezo-Sanchez et al., 2023). In particular, the development of transient wireless power and data transmission modules is crucial for progressing toward fully biodegradable wireless implants in neural applications.

To facilitate the post-surgical therapeutic effect aimed at restoring the function of injured tissues or nerves within a specified timeframe, tremendous effort has been dedicated towards the development of predefined period IMDs, including electrical stimulators and conductive nerve conduits. In this section, we explore representative examples of biodegradable implants powered by non-invasively EM-based WPT technology.

Koo et al., previously mentioned in the transient stimulation section of this review, introduced a transient wireless electrical peripheral nerve stimulation system in 2018 (Figure 10) (Koo et al., 2018). This study firstly reported the validation of its capability to facilitate neuroregeneration and recovery by stimulating injured nervous tissue. This biodegradable stimulator featuring Mg electrodes also included a power supply in the form of a bilayer Mg-based loop antenna fabricated on a PLGA dielectric layer, a silicon diode, and a Mg capacitor. The RF power harvester interfaces with the electrodes using bioresorbable sutures, wirelessly delivering electrical impulses to electrodes from an external transmitter coil at a 5 MHz operating frequency. The wireless harvester demonstrated the capability to generate a 1 V output voltage from an 11 V transmitting voltage, with an 80 mm separation between the harvester and transmitter. This meets the requirement for inducing the nerve activation, with the threshold voltage falling within the range of 100–300 mV. This study laid a crucial foundation for early post-operative recovery stage in nerve injuries by utilizing wireless bioresorbable stimulators for a well-defined duration, achieved through the selection of appropriate thicknesses of the biodegradable materials. However, the performance of inductive coupling WPT is susceptible to the distance and rotation misalignment, necessitating precise alignment between the external transmitter and the implanted receiver.

On the basis of this study, Guo et al. reported a wireless magnetic energy harvester based on a rotating magnet to enhance the robustness and reliability of the WPT link for supporting nerve stimulations (Figure 11) (Guo et al., 2019). This magnetically coupled system consisted of a power-controllable rotating permanent magnet serving as the transmitter, and a fully biodegradable Mg-based antenna designed for the implantable energy harvester, placed parallelly with the transmitter coil. By varying the rotational frequency of the magnet, the magnetic flux through the coils is induced to change, resulting in power generation in the receiver coil. The induced voltage linearly changes with the rotational frequency, favoring higher magnetic flux generation compared to a voltage-controlled oscillator, especially at low frequencies (<200 Hz). This transient WPT system can produce peak-to-peak voltages (Vp-p) over 300 mV at a distance of 4 mm at 38.5 Hz rotational frequency, which is sufficient to promote and activate neuro-regeneration. In addition, the lateral misalignment problem was mitigated by adding a biodegradable magnetic field concentrator (MFC), resulting in an approximate average 14% enhancement in Vp-p at a work distance of 4 mm across various frequencies (10 Hz–55 Hz). Nonetheless, the efficacy of the added MFC diminishes when the separation exceeds 6 mm and the frequencies are under 30 Hz, while also increasing the volume of the implantable device.

To further enhance the efficacy of hastening recovery after surgery and injuries, Huang et al. presented innovative bioresorbable microneedles that seamlessly integrate drug delivery with electrostimulation therapy (Huang et al., 2022). These microneedles, with a needle height of 900 μm, penetrate deep tissue, releasing anti-inflammatory drugs and Rhodamine during the device biodegradation within the body. This implantable and bioresorbable microneedle (IBMN) device delivers electrostimulation via a magnetic coupling-based WPT system operating at a resonant frequency of 6.6 MHz. It is constructed with a biodegradable implantable antenna, comprised of two layers of square-shaped Mg coils separated by a PLGA dielectric interlayer, and a doped silicon diode. Consequently, the IBMN device achieves an output voltage of 6.6 V at a high load resistance of 5 kΩ within a 4 cm thick porcine tissue under 1 W power transmitted from a 6 cm external coil. Additionally, this flexible implantable antenna remains robust under a banding radius of 0.9 cm. The therapeutic efficacy of the IBMN device was evaluated by applying it to rat muscle injury model, along with a negative control group. Results demonstrated that the device accelerated the tissue repair and regeneration within a mere 9-day period. However, the degradation rate of the PLGA film increases and it swells upon exposure to biofluids during implantation. This further accelerates the dissolution of the Mg antenna and the interconnect to the microneedles, ultimately impacting the electrostimulation function of the device. A possible avenue to be explored would be the use of an encapsulant to decrease the rate of degradation of the overall antenna, however this could affect the transmission of power and data through damping, hence alternatives to PLGA could also be explored, such as PCL or Poly-(3-hydroxybutyrate)(PHB).

Recently, Kim et al. introduced an electroceutical platform that combines a biodegradable Mo/PCL conductive nerve conduit (CNC) with a wireless electrical stimulator to maximize the therapeutic effectiveness for long nerve defects (Kim et al., 2023). The wireless stimulator is implanted beneath the skin of a rat to deliver monophasic pulse to the CNC by interconnecting a stainless-stell wire. It consists of an Mg inductive coil with a 2 cm diameter, a commercial Schottky diode and a capacitor, assembled and encapsulated in Ecoflex® 0030. By integrating the CNC, electrostimulation can effectively reach to the distal stump, separated by a 10 mm nerve gap, thereby accelerating axon generation. In addition, the Mo/PCL composite-based CNC enables the transmitted voltage to approximate 1 V, which is triple compared to the non-conductive PCL CNC, as depicted in Figure 12. This integrated electroceutical strategy demonstrates clear effectiveness in enhancing therapy for long peripheral nerve defects. However, the non-degradability of the wireless electrical stimulator poses a risk in terms of inflammatory effects. To address this issue, utilizing biodegradable materials-based components such as Zn-ion hybrid capacitors (Sheng et al., 2023), and Si diodes presents a viable alternative solution to ensure the platform’s complete biodegradability and to minimize adverse reactions. Moreover, the size of the implantable coil is relatively large for the implants. The study also would benefit from clarifying the transmission distance and showcasing misalignment analysis.

As an alternative to percutaneous-wire stimulation, wireless electro-stimulators powered by WPT strategies are favored for the dynamic control of the transferred power by adjusting the input power from an external transmitter. This capability distinguishes WPT technology from other passive solution such as triboelectric and piezoelectric nanogenerator, and it serves as the foundation for maintaining proper control of stimulation parameters for IMDs. However, the significant EM waves mismatch at the air and tissue interface inhibits the efficient wireless power delivery of target therapeutic moieties. Specifically, near-field WPT strategies such as inductive coupling and magnetic coupling are widely adopted for delivering the periodic stimulations to the target nerves or tissues. This is attributed to their relatively high-power transmission efficiency under the optimal transmitter and receiver matching conditions. Near-field WPT can achieve tens of volts output voltages, which is adequate for various classes of electrical stimulation and other active operations. However, the near-field WPT strategies typically entail relatively large sizes (in-centimeter level) for IMDs, and their efficiency is significantly affected by lateral or angle misalignment, making them not applicable for patients’ life. Therefore, more robust WPT links and high-performance deformable implantable devices are needed, requiring further research and development efforts.

In the context of fully biodegradable implantable devices composed of water-soluble materials, the stability of wireless powering is challenged by the inconstant degradation process and timespan of the implantable receiver. This instability is strongly affected by ambient pH, temperature, body fluids and the interactions with living tissues. Specifically, highly conductive biodegradable metals like Mg are commonly used in coil fabrication for the implantable RF receiver due to their stronger coupling and ability to receive higher output power or voltage. However, it dissolves at a faster rate (0.26 mmyear⁻¹) compared to other biodegradable materials such as polymers or ceramic-based materials, which can render the entire implant non-functional (Zhang et al., 2010; Pogorielov et al., 2017). Therefore, further advancement in highly conductive materials innovation, such as synthetic materials or the substitute biodegradable metals, or the development of encapsulation strategies based on conductive coatings, are essential to optimize the lifespan of the biodegradable RF implantable receivers, to match the electrodes and substrate ones.

From a systems perspective, wireless data transmission should be integrated into the existing combined device to establish a viable communication pathway for monitoring the effectiveness of the recovery process post-treatment.

6 Biocompatibility and response to implantable neurotechnologies

Biocompatibility refers to the capability of a biomaterial to integrate and interact with the host tissue, in the way it was intended, without causing any adverse reactions (Anderson, 2001), or in other words: “Biocompatibility is generally defined as the ability of a biomaterial, prosthesis, or medical device to perform with an appropriate host response in a specific application” (Black and Black, 2005). Biomaterials can be categorized into two main groups: bioinert and bioactive. Bioinert materials do not interact with the tissue and do not initiate a foreign body response; while bioactive materials interact with the body and may elicit an inflammatory reaction. Like any other foreign substances, transient implants that dissolve after a predetermined amount of time, also elicit a biological response within the tissue they come into contact with. The goal here is not to completely suppress the body’s response to these implants but rather minimize the foreign body reaction process in a way that allows the implant to function effectively.

Furthermore, transient implants undergo a degradation process that involves the release and excretion of by-products. To ensure the biocompatibility of an implanted device, it is crucial to understand these processes and ensure that not only the material of the device itself is biocompatible, but also that the by-products which are generated during degradation, do not pose a risk to the recipient’s health, and are excreted safely.

Putting transient neural devices into a clinical context, neurological disorders are the leading cause of disability and the second leading cause of death worldwide. With a growing number of people affected by conditions such as Alzheimer’s disease, Parkinson’s disease, epilepsy, and dementia, due to the increasing population and aging, these debilitating conditions impose significant burdens on population health and healthcare costs; and on an individual level, can lead to loss of productivity, income, and quality of life (Feigin et al., 2020; Steinmetz et al., 2024).

According to recent studies, the brain tissue reaction to implanted electrodes is the main failure mode of these devices, highlighting that biocompatibility is imperative when it comes to the design of brain implants (Polikov et al., 2005). Before a medical device can be used in clinical applications, it must first undergo a series of biological evaluations as outlined in the International Organization for Standardization (ISO) 10993 guidelines, to ensure its biocompatibility (Kullmann et al., 2022). These tests assess the device’s safety in both in vitro and in vivo environments, covering aspects such as toxicology, genotoxicity, carcinogenicity, and reproductive toxicity. Different properties of biomaterials can significantly impact the duration and severity of the foreign body response, particularly during the initial two to 4 weeks (Anderson et al., 2008). Therefore, understanding the underlying biological mechanisms can help identify key factors that influence the body’s response to implanted materials. These factors can then potentially be manipulated to mitigate the body’s response and optimize the device’s performance.

6.1 Brain tissue response to implanted biomaterials

6.1.1 Insertion injury and blood brain barrier (BBB) disruption

Mechanical injury to the brain tissue during the implantation process severs blood vessels and disrupts the BBB. This vascular damage leads to blood-material interaction and deposition of plasma proteins into the brain’s microenvironment. These proteins, which are normally excluded from the brain’s physiological milieu, contribute to the initiation of the tissue response (Figure 13) (Dávalos et al., 2000; Abdul-Muneer et al., 2015). For instance, albumin has been shown to activate glial cells, while fibrinogen inhibits axonal regrowth in damaged neurons.

In addition to protein influx, peripheral immune cells, including neutrophils and macrophages, infiltrate the injury site through compromised vasculature and contribute to the foreign body response via the release of reactive oxygen species and pro-inflammatory cytokines.

BBB disruption also affects pericytes. Pericytes are specialized cells that are embedded within vessel walls in the brain and play a crucial role in modulating the blood flow. They maintain the integrity of BBB, allowing essential nutrients to enter the brain while restricting the passage of harmful substances. They are also capable of clearing cell debris through phagocytosis (Armulik et al., 2010; Bell et al., 2010).

After implantation, pericytes detach from blood vessels and start to migrate towards the injury caused by the probe insertion, neglecting their normal responsibilities in the process (Wellman and Kozai, 2017). This leads to decreased blood flow and oxygen supply to the brain, contributing to tissue hypoxia and neuronal damage (Figure 13B)(Marchesi, 2011; Winkler et al., 2011).

Overall, this cascade of events, following implantation and BBB disruption, leads to the activation of brain cells involved in the FBR, including microglia and astrocytes, that drive the response forward (Figure 14).

6.1.2 Microglia and acute inflammation

Microglia are the resident immune cells of the brain, and they are one of the earliest responders following device implantation (Alloway, 2001; Streit, 2004). Under physiological conditions, they exhibit a highly ramified morphology, continuously surveying their local environment by extending and retracting their processes in a dynamic manner (Kreutzberg, 1996; Nimmerjahn et al., 2005).

Following injury induced by probe implantation, microglia become activated and undergo a morphological transformation characterized by retraction of their processes and acquisition of an amoeboid phenotype. Within the first 24 h, activated microglia enter a motile phase that enables migration towards the injury site, where they accumulate and form a thin cellular layer adjacent to the probe surface (Figure 13B) (Stence et al., 2001; Kozai et al., 2014). This is accompanied by proliferation, increased production of lytic enzymes, and enhanced phagocytic activity (Ling, 1981).

In addition, microglia secrete a range of cytokines and chemokines that modulate other cellular components of the FBR. They recruit additional microglia and peripheral macrophages through the release of monocyte chemoattractant protein-1 (MCP-1) (Babcock et al., 2003), a key chemokine that regulates the migration and infiltration of monocytes from the bloodstream (Deshmane et al., 2009). Activated microglia also produce pro-inflammatory cytokines, including IL-1, IL-6, and TNF-α. Sustained release of these mediators contributes to neuronal degeneration and demyelination at the implant site (Woodroofe et al., 1991; Giulian et al., 1994a; Giulian et al., 1994b; Chabot et al., 1997).

Furthermore, microglia generate reactive oxygen species (ROS) and secrete degradative enzymes, leading to increased oxidative stress within the local tissue environment. These processes contribute not only to cellular damage and neuronal loss but also to the accelerated degradation and corrosion of the implant material.

Microglial activation and response persist throughout the first week following implantation, during which they play a central role in driving the acute phase of the FBR. Sustained microglial activity and continued production of pro-inflammatory cytokines subsequently promote astrocyte activation, facilitating the transition of the FBR from the acute to the chronic phase.

6.1.3 Astrocytes and glial scar formation

Astrocytes are characterized by numerous processes that extend radially, that confer them a star-like morphology. They are essential for maintaining neuronal health and physiological function by providing both structural and biochemical support. In addition, astrocytes regulate synaptic activity by maintaining ionic homeostasis and controlling neurotransmitter levels within the extracellular space (Chen and Swanson, 2003).

Following device implantation, astrocytes are activated in response to tissue injury and undergo transformation into a reactive phenotype, characterized by cellular hypertrophy, enhanced migratory capacity, and upregulation of glial fibrillary acidic protein (GFAP) expression (Bignami et al., 1980; Eng and Dearmond, 1982; Landis, 1994). These changes, collectively referred to as reactive gliosis, prime astrocytes for an amplified response to the implanted material.

Within the first week after implantation, activated astrocytes begin to migrate towards the injury site and accumulate at the device–tissue interface (Kozai et al., 2014). Through the formation of intercellular junctions with neighboring glial cells, they progressively establish a multilayered cellular sheath surrounding the implant. Over the subsequent weeks, this structure increasingly isolates the device from the surrounding neural tissue, reducing ionic and neurotransmitter exchange and increasing the distance between the electrode interface and nearby neurons (Figure 13C) (Roitbak et al., 1999).

The formation of this dense cellular sheath, termed glial scarring, typically progresses over 4–6 weeks and can persist for years following implantation, progressively acquiring a more fibrotic structure. This encapsulation is largely irreversible and leads to functional isolation of the device from its target neurons, ultimately resulting in device failure.

6.1.4 Neuronal death around the implant

In parallel with the inflammatory response, neuronal loss occurs in tissue adjacent to the probe implantation site, driven by both initial mechanical injury and the inhospitable microenvironment generated by sustained inflammatory activity. This region, extending approximately 100 µm from the implant, exhibits a reduced neuronal density compared to the surrounding tissue. Notably, neuronal density is inversely correlated with microglial activity, such that regions closer to the implant, where microglial activation is greatest, display more pronounced neuronal loss. Longitudinal analyses further indicate that this neuronal loss expands over time as inflammation persists (Biran et al., 2005), suggesting that limiting the duration of the inflammatory response may mitigate neuronal depletion.

Considering the neural tissue responses to implanted biomaterials, ensuring the biocompatibility of biodegradable neurotechnologies, minimizing the foreign body response, and preventing adverse immune reactions are essential for achieving effective device–tissue interfacing. As the broader potential of these technologies is explored, their advantages, such as eliminating the need for device removal and improving patient outcomes, must be balanced against the remaining technical and regulatory challenges that need to be addressed to enable successful clinical translation.

7 Strengths, limitations, and future directions of biodegradable neurotechnologies

The use of transient electronics in neurological applications reduces the need for surgical explantation following the device’s functional lifetime, thereby minimising associated risks and patient discomfort. This approach is particularly well suited to temporary neurological interventions, such as sEEG epilepsy monitoring and post-stroke rehabilitation, where devices are required only for a defined period of recording and neuromodulation.

Despite these advantages, several challenges remain, particularly with respect to fabrication complexity and long-term stability, given the inherent fragility of degradable materials and the relative immaturity of biodegradable technologies. In this section, these advantages and limitations are examined to provide a comprehensive outlook on the future development and clinical translation of dissolvable neurotechnologies.

7.1 Temporary existence

It is well established that the prolonged presence of implanted devices in brain tissue elicits a sustained inflammatory response, leading to the formation of a dense glial scar, pronounced neuronal loss, and a progressive decline in device performance (Weldon et al., 1998; Biran et al., 2005; Kozai et al., 2015).

The effectiveness of the electrode-brain interface is closely linked to the distance between the electrode and its target neurons, as close proximity is required for efficient recording and stimulation (Polikov et al., 2005). Glial scarring increases this separation, thereby compromising device functionality. To better isolate the effects of chronic implantation, several studies have compared long-term electrode implants with “stab wound” models, in which the same implantation procedure is performed but the electrode is immediately withdrawn. This approach distinguishes the impact of the initial mechanical injury from that of the sustained presence of the device. These studies demonstrate that, in stab wound models, microglial and astrocytic activation is significantly reduced, and neuronal loss is largely limited to the initial injury, in contrast to chronically implanted electrodes. Collectively, these findings indicate that ongoing inflammation, rather than the initial insertion trauma alone, is the primary driver of glial scarring and neurodegeneration (Biran et al., 2005).

In this context, transient electronics offer an inherent advantage over chronically implanted devices, as they are designed to degrade and resorb after a defined functional period. This temporary presence has the potential to reduce the duration of the foreign body response and limit long-term tissue damage associated with conventional implants.

In addition, infection remains a significant challenge for chronic neural implants, as their persistent presence can provide a nidus for bacterial colonization (Chen et al., 2019). In contrast, biodegradable probes, by virtue of their degradation over time, are less likely to support sustained microbial growth.

7.2 Avoiding secondary retrieval interventions

Implant failure can arise from several mechanisms, including tissue reactions, infection, or device malfunction. For chronic implants, failure necessitates secondary surgery for device retrieval; procedures that compound clinical risk and place considerable financial strain on patients and healthcare providers alike. The use of biodegradable materials offers a compelling alternative, as such implants are naturally resorbed by the surrounding tissue, rendering retrieval surgery unnecessary (Cha et al., 2019).

7.3 Challenges remaining

Despite the advantages outlined above, significant challenges remain in the clinical translation of biodegradable neural devices. Firstly, the fabrication of flexible, biodegradable systems is often incompatible with conventional microfabrication techniques used for solid-state electronics. Established processes, such as photolithography, expose degradable materials to harsh conditions, including elevated temperatures, mechanical stress, and aggressive chemicals. This incompatibility compromises material integrity, introduces variability in device performance, and hinders scalable manufacturing.

In addition, these devices must maintain reliable functionality throughout the intended treatment period. However, biodegradable implants are inherently susceptible to early degradation, delamination, and mechanical failure, which may lead to early loss of function and suboptimal therapeutic outcomes. For biodegradable technologies to achieve widespread adoption, advances in materials science are needed to enable precise control over degradation kinetics while preserving functional stability over clinically relevant timescales. Furthermore, the development of fabrication methods specifically tailored to biodegradable materials will be essential to ensure scalable, high-quality manufacturing that meets regulatory standards.

From a regulatory perspective, successful clinical translation requires demonstration of safety and efficacy in a consistent and reproducible manner. The current biological evaluation framework for medical devices, anchored in ISO 10993 (Thangaraju and Varthya, 2022), was developed primarily around the model of a stable bulk material from which only limited, unwanted leaching or degradation occurs. Fully biodegradable and bioresorbable devices are regulated under the same general frameworks as conventional devices, with no dedicated horizontal standards of their own; instead, they are treated as higher-risk, scientifically complex products required to demonstrate additional evidence for degradation kinetics, identification and quantification of degradation products, local and systemic toxicity, mechanical stability throughout resorption, long-term safety, sterility, shelf life, and clinical performance over the entire functional and resorption lifetime. The absence of harmonised test methods for these endpoints produces inconsistent protocols across sponsors and considerable uncertainty during conformity assessment.

The full-degradation profile creates several distinctive challenges that are specific to bioresorbable devices. The volume and chemical diversity of degradation byproducts generated over the device lifetime is significantly greater than for permanent implants, requiring more comprehensive toxicokinetic and biocompatibility characterisation under ISO 10993-16 (International Organization for Standardization ISO, 2017) and -17 (International Organization for Standardization ISO, 2023). A fundamental difficulty that regulators currently struggle to resolve is the accurate prediction of long-term in situ degradation behaviour. Accelerated aging studies do not necessarily reproduce in vivo kinetics, animal models translate imperfectly to human physiology, and degradation rates can vary substantially between individual patients. In vitro degradation testing, typically conducted in PBS at physiological pH and temperature, is particularly limited for neural devices, where it fails to capture the distinct ionic and protein composition of cerebrospinal fluid, enzymatic degradation by enzymes present in brain interstitial fluid, oxidative degradation arising from inflammation and the FBR, and the patient- and disease-specific pH shifts encountered in pathological tissue (Tamariz and Rios-Ramírez, 2013). These limitations together explain why in vitro to in vivo correlation (IVIVC) remains an active gap in the standards landscape.

Beyond the difficulty of characterising degradation behaviour, the degradable nature of these devices carries direct clinical and operational consequences. Premature degradation, whether driven by manufacturing variability, storage conditions, sterilisation effects (with the current gold standard being ethylene oxide sterilisation) (Dai et al., 2016), or patient-specific factors, can shorten the effective therapeutic window, demanding rigorous post-market surveillance and tightly controlled distribution and handling. This concern is particularly acute for closed-loop systems incorporating AI/ML signal processing, in which models are typically trained on the assumption of stable sensing performance and do not account for the gradual signal drift that accompanies in situ degradation (Sussillo et al., 2016). Collectively, these factors argue for dedicated standards within the FDA and European Union Medical Device Regulation (EU MDR) frameworks for fully degradable active implantable medical devices (AIMD), establishing harmonised testing, verification, and validation methods to replace the largely consultative, case-by-case approach currently negotiated between regulators and legal manufacturers.

At the time of writing, no active biodegradable CNS-implantable device has received either an Investigational Device Exemption (IDE) for clinical investigation or marketing authorisation for commercial use in any major jurisdiction. The biodegradable neural interfaces currently certified are limited to PNS applications, such as peripheral nerve guide conduits for nerve repair (Tabatabai et al., 2025). The absence of established predicate devices effectively shuts down the 510(k) pathway in the United States, and the Class III risk profile of implantable CNS devices excludes them from the De Novo classification route. This leaves Premarket Approval (PMA) in the US and full Notified Body conformity assessment under EU MDR Annex IX as the only viable pathways, both of which are time- and resource-intensive, and particularly burdensome for the start-ups and small-to-medium enterprises that typically translate these technologies from academic research into clinical practice.

Addressing these challenges will require parallel action on two fronts. First, harmonised standards tailored specifically to fully bioresorbable AIMD must be developed and adopted across major jurisdictions, providing consistent requirements and validation methodologies for the field. Second, the early commercialisation phase, when predicate devices and accumulated clinical evidence remain sparse, must be assisted through accelerated, resource-supported regulatory pathways. The FDA’s Breakthrough Device Designation (Breakthrough Devices Program: Guidance for Industry and Food and Drug Administration Staff, 2023), which provides interactive engagement with the Agency and prioritised review, is a useful template, and equivalent mechanisms should be expanded within other jurisdictions. In fact, as of the time of writing, the EU has now launched a pilot programme “EU Breakthrough Device Designation (BtX)” providing expert panel advice for developers of breakthrough medical devices and in vitro diagnostic medical devices (Medical Device Coordination Group MDCG, 2025). As more devices progress through clinical investigation and into routine clinical use, the resulting body of regulatory precedents and real-world evidence will progressively de-risk certification for the next-generation of transient medical devices.

8 Conclusions and future directions in transient neurotechnology

The emergence of biodegradable and bioresorbable devices marks a significant leap forward in the field of implantable neurotechnology, offering solutions that minimize long-term risks and reduce the need for secondary surgical procedures. Transient electronics, particularly in neural probes for recording and stimulation, provide novel opportunities for temporary interventions that degrade safely within the body after serving their clinical purpose. Advances in transient power supply strategies, such as biodegradable energy harvesters and wireless power transfer systems, further enhance the functionality and autonomy of these devices without the need for permanent, invasive power sources. While these developments showcase immense potential, ongoing research is required to optimize material properties, ensure controlled degradation rates, and balance performance with safety across a broad range of neural applications.

Looking ahead, future directions in transient neurotechnology are expected to focus on refining device durability and adaptability to meet specific medical needs, including customizing degradation timelines for different therapeutic interventions. Researchers will likely explore more sophisticated integration of transient devices with biological systems, potentially developing multi-modal platforms that combine neural recording, stimulation, and drug delivery within a single biodegradable interface. Close collaboration between material scientists, biomedical engineers, and clinical neurologists/neurosurgeons will be essential to address existing challenges, such as sustained biocompatibility, the safe excretion of degradation by-products, and scalability for widespread clinical use, including surgical implantation strategies. Furthermore, regulatory frameworks will need to evolve to account for this novel class of medical devices, ensuring patient safety while allowing for a more rapid translation from lab to clinic.

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Footnotes

Edited by: Shiwei Wang, The University of Edinburgh, United Kingdom

Reviewed by: Hongwei Sheng, Lanzhou University, China

Sung-Yun Park, Pusan National University, Republic of Korea